Denosumab


Article Author:
Gregory Hildebrand


Article Editor:
Anup Kasi


Editors In Chief:
Mark Pellegrini


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
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Radia Jamil
Erin Hughes
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Navid Mahabadi
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Heba Mahdy
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
12/13/2018 11:07:40 AM

Indications

Denosumab is a bone anti-resorptive drug used for the treatment of the following: 

FDA-approved indications:

  1. Prevention of skeletal-related events (e.g., bone pain and fractures) secondary to multiple myeloma or bone metastases from solid tumors. Used in conjunction with treatment of primary malignancy[1]
  2. Giant cell tumor of the bone. Indicated in adults and skeletally mature adolescents that have an unresectable tumor or when surgical resection would likely cause severe morbidity.[2]
  3. Hypercalcemia of malignancy. Indicated when hypercalcemia is refractory to bisphosphonate therapy.
  4. Osteoporosis. Indicated as therapy for postmenopausal women with osteoporosis at high risk for fracture. It is also indicated for the treatment of men with osteoporosis at high risk of fracture. A high risk for fracture is defined as those with multiple risk factors for fracture, a known history of an osteoporotic fracture,  or those who have failed prior osteoporosis treatment (e.g., bisphosphonates).[3]
  5. Glucocorticoid-induced osteoporosis. Indicated for treatment in patients of both sexes at high risk for fracture who are initiating or continuing systemic glucocorticoids at a dose greater than or equal to 7.5 mg of prednisone daily for an expected duration of at least six months.[4]
  6. Bone loss. Indicated for the treatment of androgen deprivation-induced bone loss and aromatase inhibitor-induced bone loss. The goal of treatment is to increase bone mass in men with prostate cancer receiving androgen deprivation therapy. In women, the treatment goal is to increase bone mass when receiving aromatase inhibitor therapy for breast cancer.[5]

Mechanism of Action

Denosumab is a total human IgG2 monoclonal antibody that binds to receptor activator of NF kappa B ligand (RANKL) and competitively inhibits its binding to receptor activator of NF kappa B (RANK). Soluble RANKL is a trimer and a member of the tumor necrosis factor (TNF) family of ligands. Each RANKL trimer can bind and oligomerize up to three receptors. When bound to RANK, RANKL potentiates osteoclast differentiation from hematopoietic stem cells and activates and prolongs the survival of mature osteoclasts. Osteoclasts primary function then is to promote bone resorption. Denosumab binds to RANKL with high affinity and blocks it from binding to and oligomerizing its receptor RANK, thus inhibiting osteoclast maturation and bone resorption. 

Administration

Administer via subcutaneous injection only and should not be administered via intravenously or intramuscularly. Injection sites include the upper arm, upper thigh, or abdomen. No observation or premedication is required. Dosing is prescribed as 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial or as a single-use pre-filled syringe containing 60 mg in a 1 mL solution. Administer vitamin D and calcium as necessary to treat or prevent hypocalcemia — no dosing adjustments required for hepatic or renal impairment. The distribution and timing of doses depend on the pathology as shown below. 

  • Skeletal-related events secondary to multiple myeloma or bone metastases from solid tumors: administer 120 mg injection every four weeks
  • Giant cell tumor of bone: 120 mg injection administered every four weeks with supplementary doses of 120 mg on the 8th and 15th day during the first month of treatment
  • Hypercalcemia of malignancy: administer 120 mg injection every four weeks with supplemental doses of 120 mg on the 8th and 15th day during the first month of treatment
  • Osteoporosis/bone loss: administer 60 mg every six months

Adverse Effects

Adverse effects include the following based on body systems:

Cardiovascular:

  • Peripheral edema (4% to 20%)
  • Hypertension (5%)
  • Angina pectoris (4%)

Central nervous system:

  • Fatigue (45% or less)
  • Headache (18%)
  • Sciatica (6%)

Dermatologic:

  • Skin rash (14% or less)
  • Dermatitis (11% or less)
  • Eczema (11% or less)

Endocrine:

  • Hypophosphatemia (32%)
  • Severe hypophosphatemia (15%)
  • Hypocalcemia (3% to 10%)
  • Hypercholesterolemia (8%)
  • Grade 3 hypokalemia (4%)
  • Grade 3 hypomagnesemia (4%)
  • Severe (symptomatic) hypocalcemia (<1% to 3%)

Gastrointestinal:

  • Diarrhea (34%)
  • Nausea (31%)
  • Decreased appetite (25%)
  • Vomiting (25%)
  • Constipation (22%)
  • Flatulence (3%)

Hematologic and oncologic:

  • Anemia (22%)
  • Thrombocytopenia (20%)
  • New malignant neoplasm (4%)

Infection:

  • Serious infection (5%)

Neuromuscular and skeletal:

  • Weakness (45% or less)
  • Back pain (15%)
  • Arthralgia (11%)
  • Limb pain (11%)
  • Musculoskeletal pain (7%)
  • Ostealgia (5%)
  • Myalgia (4%)
  • Osteonecrosis of the jaw (1% to 4%)[6]

Ophthalmic:

  • Cataract (5% or less)

Respiratory:

  • Dyspnea (24%)
  • Cough (16%)
  • Upper respiratory tract infection (6% to 16%)
  • Pneumonia (9%)
  • Nasopharyngitis (8%)

Contraindications

  • Known severe hypersensitivity to denosumab or any component of the formulation 
  • Preexisting hypocalcemia 
  • Pregnancy 

Monitoring

Possible pregnancy should be evaluated before initiation of treatment. Obtaining vitamin D level and clearance from a dentist is suggested before the initiation of therapy. Within the first few weeks of treatment, recommended monitoring of serum creatinine, calcium, phosphorus, and magnesium. Monitor for signs and symptoms of hypocalcemia as well as hypercalcemia upon discontinuation of denosumab. A dental exam should is recommended if osteonecrosis of the jaw is suspected. The evaluation of bone mineral density should occur anywhere between one to two years after initiating treatment. The recommendation is for periodic monitoring of vitamin D and serum calcium throughout treatment duration.[7][8]

Toxicity

Atypical bone fractures: Although the incidence remains low, an association with atypical bone fractures exists with prolonged bisphosphonate therapy. However, these fractures have also been observed in those receiving denosumab for osteoporosis or metastatic bone disease. These fractures are usually located in the subtrochanteric region or along the shaft of the femur. Patients tend to feel prodromal pain from weeks to months leading up to the fracture. Fractures commonly occur with little to no trauma in the area. Experts are unsure at this time if the atypical fractures occur secondary to denosumab toxicity or the patient’s underlying osteoporosis. Patients should receive counseling regarding the potential for new hip or thigh pain and the contralateral limb examined if an atypical fracture is suspected. Upon diagnosis of an atypical fracture, possible discontinuation of denosumab is an option. If discontinued, consider initiating a different osteoporosis therapy due to an increased risk of fracture.[9]

Hypersensitivity: Clinically severe and anaphylactic reactions have been reported. Symptoms may include rash, pruritus, urticaria, facial edema, airway edema, and possibly hypotension. If these symptoms occur, initiate appropriate treatment and subsequently discontinue denosumab. 

Hypocalcemia: Due to its anti-resorptive effects, denosumab has the potential to cause hypocalcemia. Severe, even fatal, cases of denosumab-induced hypocalcemia have been documented. Those with severe renal dysfunction may have an increased risk of developing hypocalcemia. Serum calcium should be obtained, and preexisting hypocalcemia corrected at the initiation of treatment. In patients with preexisting hypocalcemia, serum calcium should be monitored more frequently. Use denosumab with caution in those who have predisposing conditions to hypocalcemia.[10]

Osteonecrosis of the jaw (ONJ): Reports of ONJ have been observed in those receiving denosumab. Symptoms may include jaw pain, tooth infection, bone, and gingival erosion, toothache. An increased risk of being diagnosed with ONJ correlates directly to the duration of denosumab exposure. Those with predisposing factors, such as poor dentition and recent tooth extraction, are at a higher risk. If ONJ is suspected, make arrangements for a thorough dental exam. Risk of ONJ is considerably higher in patients with malignancy receiving denosumab than in patients with osteoporosis receiving denosumab. Denosumab should not be initiated until dental health is optimized. While on denosumab for cancer therapy, dental procedures are contraindicated. If ONJ is suspected, denosumab should be discontinued.[6]

Dermatologic reactions: Reports of dermatitis, eczema, and rash have been observed. If symptoms are severe, consider discontinuation of denosumab.

Enhancing Healthcare Team Outcomes

Healthcare workers including primary care physicians and nurse practitioners who prescribe denosumab should monitor the patients. Pharmacists should assist in monitoring for side effects. The patient should get a baseline evaluation from the dentist prior to initiating treatment. At regular intervals, the patient's electrolytes and renal function should also be monitored. The most severe complication of therapy is osteonecrosis of the jaw, and thus an oral exam is necessary at each visit. Periodic bone density evaluation every 1-2 years is recommended. Only through close monitoring of the patient can the morbidity of this agent be decreased.


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Denosumab - Questions

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A 57-year-old female with a past medical history of hypertension, chronic kidney disease with a creatinine clearance of 30 mL per minute, and type 1 diabetes mellitus presents to the office after recovering from a hip fracture. She states the fracture occurred after tripping on a rug in her home. She states she has a history of falls secondary to her peripheral neuropathy. She has osteoporosis. Which of the following treatments to help improve her bone mineral density?



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A 65-year-old male patient with known prostate cancer presents with a chief complaint of lower back pain. Physical exam elicits bony tenderness along the lumbar spine. Radiology reveals bony metastases to the L3-L5 vertebrae. Which medication competitively inhibits the binding of RANKL to RANK and is FDA-approved to treat bony metastases from solid tumors?



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A 25-year-old male with no known past medical history presents for an acute visit. He reports right knee pain that is progressive and started "months" ago. He denies any trauma to his knee and doesn't remember when he first noticed it. Physical exam reveals tenderness to palpation on the anteromedial aspect of the distal femur with associated edema, erythema, and soft-tissue expansion. Anterior and posterior drawer test both negative. No pain is elicited when the knee is put under valgus or varus stress. An anteroposterior radiograph of the right distal femur revealed an expansile lytic metaphyseal-epiphyseal lesion. The diagnosis of giant cell tumor was made, and treatment with denosumab was initiated. What is the recommended dosing for this specific patient?



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A 65-year-old female with a past medical history of hypertension, type 2 diabetes mellitus, osteoporosis, and known breast cancer status post surgical intervention and chemotherapy presents for an acute visit. She reports having right hip pain for the last few weeks but had an acute increase in this pain when she was walking yesterday. She denies any other trauma to the area and states that anti-inflammatories have not improved her pain. Her current medications include simvastatin, lisinopril, hydrochlorothiazide, metformin, trastuzumab, and denosumab. Physical exam reveals a shortened and externally rotated right lower extremity with tenderness to palpation on the lateral aspect of her hip. A plain x-ray reveals a subtrochanteric transverse fracture. By what mechanism of action has this pathology occurred?



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A 72-year-old male with a past medical history of hypertension, hyperlipidemia, and known prostate cancer with metastases to the bone presents to the emergency department after an acute onset of confusion. His son provided most of the history. He states that his father had recently switched from bisphosphonate therapy to denosumab for his uncontrolled bone pain. He reports over the last week or so his father had been reporting a tingling sensation around his mouth and fingertips as well as an increase in leg swelling. Then this morning his father woke up and seemed to be confused, not knowing where he was or his son's name. Physical exam reveals bilateral lower extremity edema and a positive Trousseau and Chvostek signs. What laboratory test should have been obtained prior to initiating denosumab?



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Denosumab - References

References

Ahern E,Smyth MJ,Dougall WC,Teng MWL, Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy. Nature reviews. Clinical oncology. 2018 Sep 19     [PubMed]
Tsourdi E,Makras P,Rachner TD,Polyzos S,Rauner M,Mandanas S,Hofbauer LC,Anastasilakis AD, Denosumab effects on bone density and turnover in postmenopausal women with low bone mass with or without previous treatment. Bone. 2018 Oct 4     [PubMed]
Briot K,Paccou J,Beuzeboc P,Bonneterre J,Bouvard B,Confavreux CB,Cormier C,Cortet B,Hannoun-Lévi JM,Hennequin C,Javier RM,Lespessailles E,Mayeur D,Artus PM,Vieillard MH,Debiais F, French Recommendations for Osteoporosis Prevention and Treatment in Patients with Prostate Cancer Treated by Androgen Deprivation. Joint, bone, spine : revue du rhumatisme. 2018 Oct 1     [PubMed]
Otto S,Pautke C,Van den Wyngaert T,Niepel D,Schiødt M, Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer treatment reviews. 2018 Sep     [PubMed]
Starr J,Tay YKD,Shane E, Current Understanding of Epidemiology, Pathophysiology, and Management of Atypical Femur Fractures. Current osteoporosis reports. 2018 Aug     [PubMed]
Imatoh T,Sai K,Takeyama M,Hori K,Karayama M,Furuhashi K,Segawa K,Kimura M,Kawakami J,Saito Y, Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia. Journal of clinical pharmacy and therapeutics. 2018 Aug 24     [PubMed]
Chung TL,Chen NC,Chen CL, Severe hypophosphatemia induced by denosumab in a patient with osteomalacia and tenofovir disoproxil fumarate-related acquired Fanconi syndrome. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018 Aug 31     [PubMed]
Saleem S,Patel S,Ahmed A,Saleem N, Denosumab causing severe, refractory hypocalcaemia in a patient with chronic kidney disease. BMJ case reports. 2018 May 30     [PubMed]
Jamshidi K,Gharehdaghi M,Hajialiloo SS,Mirkazemi M,Ghaffarzadehgan K,Izanloo A, Denosumab in Patients with Giant Cell Tumor and Its Recurrence: A Systematic Review. The archives of bone and joint surgery. 2018 Jul     [PubMed]
Iwamoto N,Okamoto M,Tsuji S,Endo Y,Takatani A,Shimizu T,Umeda M,Fukui S,Sumiyoshi R,Igawa T,Koga T,Kawashiri SY,Aramaki T,Ichinose K,Tamai M,Nakamura H,Origuchi T,Eguchi K,Ueki Y,Kawakami A, Denosumab is effective toward glucocorticoid-induced osteoporosis patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drugs. Journal of bone and mineral metabolism. 2018 Sep 5     [PubMed]

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